There is a dramatic and unexplained racial/ethnic disparity in prostate cancer in the US. African Americans (AA) are 1.6 times more likely to be diagnosed with prostate cancer and 2.4 times more likely to die from prostate cancer than Caucasian Americans (CA). While it is likely that multiple factors account for this disparity, genetic predisposition may account for a substantial proportion. We have discovered that inherited mutations in the mitochondrial genome are associated with an increased risk of prostate cancer and that AA males have very different mutations in this genome than CA and that AA men have significantly greater rates of mitochondrial DNA (mtDNA) mutations than CA. The overall hypothesis we will test is that race-specific missense mtDNA mutations that are found in the germ line of AA and CA men with prostate cancer alter mitochondrial biology so as to enhance prostate cancer growth and survival. Because of our ongoing 10-year prospective specimen banking protocol we have biologic specimens (including peripheral blood DNA) and clinical data on over 1000 men that have undergone radical prostatectomy for prostate cancer at Emory University Hospital. Because of technical advances in mtDNA sequencing, the entire mitochondrial genome (~16.5 kb) can be rapidly and reliably sequenced by chip based methods. We are therefore uniquely positioned to rapidly perform sequencing of the entire mitochondrial genome in AA and CA men with prostate cancer and propose sequencing 50 men from each racial group and comparing the mtDNA mutations. All individuals with missense mutations will be contacted for further phlebotomy and the establishment of lymphoblast cell lines that will allow us to "capture" these mtDNA mutations and generate prostate cancer cell lines with prostate cancer relevant mtDNA mutations. Each mutation will be paired with an appropriate control cell line that differs by a single mtDNA base change. These mutant/control pairs will then undergo analysis of respiratory complex activity and reactive oxygen species (ROS) generation thereby allowing us to assign functionality of the observed mutations. We will also test antioxidant and anti-inflammatory agents for their ability to reverse the cell biologic derangements caused by the prostate cancer specific mtDNA mutations. If successful, these studies will define the functionality of mtDNA mutations in prostate cancer, the role they play in the racial disparity of prostate cancer, and begin to determine treatments that may be particularly effective in preventing mtDNA mutation induced cancer predisposition allowing mutation-specific treatments to be selected. The potential impact is far reaching because mitochondrial variation has now been identified as an important feature of cancer, heart disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, diabetes and optic neuropathy, all associated with mitochondrial mutations. PUBLIC HEALTH RELEVANCE: This project will study racial differences (health disparities) in prostate cancer genetics. Specifically, we will determine all mutations in the mitochondrial DNA in a group of African American and Caucasian American men with prostate cancer. Once mutations are identified they will be studied in the laboratory to determine how they exert their effects on cancer and what anti-cancer drugs might be used to treat patients with these mitochondrial DNA mutations. The ultimate use of this research is both to understand the basic abnormalities that account for racial differences in prostate cancer and to identify mutation-specific treatments.